Related Experiment Video

Updated: Nov 11, 2025

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
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Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

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An early look at selective RET inhibitor resistance: new challenges and opportunities

Jessica J Lin1, Justin F Gainor2

  • 1Center for Thoracic Cancers, Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA, USA.

British Journal of Cancer
|March 24, 2021
PubMed

Insights

Resistance to new RET inhibitors for lung cancer can arise from RET mutations or other, independent mechanisms. Understanding these resistance pathways is crucial for future treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Recent approval of selpercatinib and pralsetinib for advanced RET fusion-positive lung cancer.
  • Acquired resistance to targeted therapies presents a significant clinical challenge.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to RET inhibitors in lung cancer.
  • To identify both RET-dependent and RET-independent resistance pathways.

Main Methods:

  • Analysis of patient samples and cell models.
  • Genomic profiling to identify resistance mutations.
  • Functional assays to assess resistance mechanisms.

Main Results:

  • Acquired resistance can be driven by recurrent RET kinase domain mutations.
  • In a majority of cases, resistance is mediated by RET-independent mechanisms.
  • Identified specific RET-independent pathways contributing to treatment failure.

Conclusions:

  • Resistance to RET inhibitors is complex and multifactorial.
  • Targeting RET kinase domain mutations alone may not overcome all resistance.
  • Further research into RET-independent mechanisms is essential for developing next-generation therapies.

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